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Bone marrow-derived microglia infiltrate into the paraventricular nucleus of chronic psychological stress-loaded mice
Koji Ataka1, Akihiro Asakawa, Kanna Nagaishi
1Department of Anatomy, Sapporo Medical University School of Medicine, Sapporo, Japan.
Background:
Microglia of the central nervous system act as sentinels and rapidly react to infection or inflammation. The pathophysiological role of bone marrow-derived microglia is of particular interest because they affect neurodegenerative disorders and neuropathic pain. The hypothesis of the current study is that chronic psychological stress (chronic PS) induces the infiltration of bone marrow-derived microglia into hypothalamus by means of chemokine axes in brain and bone marrow.
Methods And Findings:
Here we show that bone marrow-derived microglia specifically infiltrate the paraventricular nucleus (PVN) of mice that received chronic PS. Bone marrow derived-microglia are CX3CR1(low)CCR2(+)CXCR4(high), as distinct from CX3CR1(high)CCR2(-)CXCR4(low) resident microglia, and express higher levels of interleukin-1β (IL-1β) but lower levels of tumor necrosis factor-α (TNF-α). Chronic PS stimulates the expression of monocyte chemotactic protein-1 (MCP-1) in PVN neurons, reduces stromal cell-derived factor-1 (SDF-1) in the bone marrow and increases the frequency of CXCR4(+) monocytes in peripheral circulation. And then a chemokine (C-C motif) receptor 2 (CCR2) or a β3-adrenoceptor blockade prevents infiltration of bone marrow-derived microglia in the PVN.
Conclusion:
Chronic PS induces the infiltration of bone marrow-derived microglia into PVN, and it is conceivable that the MCP-1/CCR2 axis in PVN and the SDF-1/CXCR4 axis in bone marrow are involved in this mechanism.
Insights
Chronic psychological stress (PS) drives bone marrow-derived microglia into the brain's paraventricular nucleus (PVN). This infiltration, linked to neuroinflammation, is mediated by specific chemokine pathways in the brain and bone marrow.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Microglia Biology
Background:
- Microglia, the brain's immune cells, respond to infection and inflammation.
- Bone marrow-derived microglia are implicated in neurodegenerative diseases and pain.
- Chronic psychological stress (PS) is hypothesized to influence microglial infiltration into the hypothalamus.
Purpose of the Study:
- To investigate the infiltration of bone marrow-derived microglia into the hypothalamus under chronic psychological stress.
- To elucidate the underlying chemokine signaling pathways involved in this process.
Main Methods:
- Analysis of microglia phenotype (CX3CR1, CCR2, CXCR4) in mice subjected to chronic PS.
- Measurement of chemokine expression (MCP-1, SDF-1) in the paraventricular nucleus (PVN) and bone marrow.
- Assessment of monocyte populations in peripheral circulation.
- Pharmacological blockade of CCR2 and β3-adrenoceptors to evaluate their role in microglial infiltration.
Main Results:
- Bone marrow-derived microglia specifically infiltrated the PVN in mice exposed to chronic PS.
- These infiltrating microglia exhibited a distinct phenotype (CX3CR1(low)CCR2(+)CXCR4(high)) and altered cytokine expression (higher IL-1β, lower TNF-α).
- Chronic PS increased MCP-1 in PVN neurons, decreased SDF-1 in bone marrow, and elevated circulating CXCR4(+) monocytes. CCR2 or β3-adrenoceptor blockade inhibited PVN microglial infiltration.
Conclusions:
- Chronic psychological stress induces bone marrow-derived microglia infiltration into the PVN.
- The MCP-1/CCR2 axis in the PVN and the SDF-1/CXCR4 axis in the bone marrow are implicated in mediating this stress-induced microglial migration.
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